The ACE2 Sheddase, ADAM17, is Up‐Regulated in Diabetic db/db Mice

Abstract

Our previous studies demonstrated loss of ACE2 in the pancreas during progression of diabetes contributes to β‐cell dysfunction and hyperglycemia. The exact mechanism behind the reduction of ACE2 is not known. A sheddase ADAM17 (a disintegrin and metalloprotease 17), can promote cleavage of the ectodomain of ACE2. The aim of this study is to test the role of ADAM17 in the regulation of cellular ACE2 levels in a diabetic mouse model. For this purpose, we used 12 week old db/db (BKS.Cg‐Dock7<m>+/+Lepr<db>/J) mice (n=4/group) and their age‐matched heterozygous controls. Diabetic db/db mice showed hyperglycemia (db/db: 202.8 ±16.6 vs. Control: 85.5 ±10.4 mg/dl p<0.05) and increased body weight (db/db: 46.04 ±0.8 vs. Control: 26.7 ±0.7 g p<0.05). In addition, quantitative RT‐PCR showed 50% reduction (p<0.05) in INS‐2 (Insulin 2) gene expression in isolated pancreatic islets of db/db mice compared to controls. There was no difference in ACE2 and ADAM17 mRNA levels, suggesting that transcriptional regulation of these targets is not glucose sensitive. However, this was associated with a significant increase in ADAM17 activity (db/db: 36.92 ±2.12 vs. Control: 11.4 ±8.2 FU/min/µg protein p<0.05) but no significant difference (p>0.05) in ACE2 activity in the islets of db/db mice. In conclusion, while our results suggests that ADAM17 is up‐regulated in db/db diabetic mice, the role of ACE2 as a potential target remains uncertain. New transgenic mice with beta‐cells specific knockdown of ADAM17 are being developed to clarify the relationship between ACE2 and ADAM17 in type 2 diabetes.Support: American Heart Association: 12EIA8030004 and 14PRE18830012.